The signaling network defined by phosphoinositide 3-kinases (PI3Ks), the serine/threonine kinases AKT (or PKB) and mammalian target of rapamycin (mTOR) is involved in many essential cellular functions including cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking (Nat. Rev. Genet. 2006, 7, 606-619; Nat. Rev. Drug Discov. 2009, 8, 627-644). To date, eight mammalian PI3Ks have been identified, which can be divided into three classes (class I, II, and III) based on their primary structure, regulatory subunits, and in vitro lipid substrate specificity. The main PI3-kinase isoform in cancer is class I PI3Ks, and the class I PI3Ks are most extensively studied.
Activated by receptor tyrosine kinases and G protein-coupled receptors (GPCRs), class I PI3Ks utilize ATP to phosphorylate the 3-OH of the inositol ring moiety, converting phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3) (Biochem. Soc. Trans. 2004, 32, 893-898), a potent secondary messenger that results in the activation of several downstream effectors, including AKT. Dysfunctional regulation of the various phosphoinositides has been implicated in a variety of diseases including cancer, autoimmune disorders, and inflammation (Nature 2006, 443, 651-657; Curr. Opin. Immunol. 2000, 12, 282-288). Thus, class I PI3Ks are attractive targets for drug discovery and development, and inhibitors of class I PI3Ks could be useful to treat a wide range of disorders such as autoimmune, inflammatory and allergic diseases, asthma, COPD, parasitic infections, diabetes and cancer (see: e.g., J. Immunol. 2007, 178, 2328-2335; Blood 2006, 107, 642-650; Blood 2004, 103, 3448; J. Allergy Clin. Immunol. 2006, 118, 403; Lancet. 1992, 339, 324; Nature 2004, 431, 1007; J. Immunol. 2008, 180, 2538; J. Immunol. 2008, 180, 870; Am. J. Respir. Crit. Care Med. 2009, 179, 542; Future Med. Chem. 2013, 5, 479; Curr. Biol. 2002, 12, 236).
The initial purification and molecular cloning of PI3Ks revealed that it was a heterodimer consisting of p85 and p110 subunits (Cell 1991, 65, 91-104; Cell 1992, 70, 419-29). Since then, four distinct class I PI3Ks have been identified, designated PI3K α, β, δ, and γ, each comprising a 110 kDa catalytic subunit and a smaller associated regulatory subunit. Class Ia PI3Ks (α, β, and δ) containing the catalytic subunits p110α, p110β, and p110δ, respectively, are activated through tyrosine kinase signaling. In contrast, the sole class Ib member, PI3Kγ, contains catalytic subunit p110γ associated with either a p101 or p84 regulatory subunit, and is mostly activated through GPCRs. While PI3Kα and PI3Kβ are ubiquitously expressed, PI3Kδ and PI3Kγ are found in leukocytes (B and T cells, and myeloid lineage cells) with PI3Kδ nearly confined to spleen, thymus, and peripheral blood leukocytes (PLoS One 2007, 2(9), e869; Trends Biochem. Sci. 2009, 34, 115). The dysregulation of PI3Kα and PI3Kρ is implicated in the etiology of solid tumors, and the dysregulation of PI3Kδ and PI3Kγ has been implicated in diseases of the innate and adaptive immune system such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and hematological malignancies. Thus selective inhibitors of PI3Kδ and/or dual PI3Kδ/PI3Kγ could provide promising therapeutic benefits to a wide variety of patients.
The central role of PI3Ks activation in tumour cell biology has prompted quite extensive drug hunting efforts, which has led to the discovery of compounds targeting PI3Ks, including downstream kinases such as AKT and mammalian target of rapamycin (mTOR) in cancer (e.g., Oncogene 2008, 27, 5511-5526; J. Clin. Invest. 2011, 121, 1231-1241; Cancer Res. 2010, 70, 2146-2157; J. Med. Chem. 2015, 58, 480; WO2005/113556; WO2008/118468; U.S. Pat. No. 8,828,998B2); however, challenges remain, and emerging clinical data show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses (Nat. Rev. Drug Discov. 2014, 13, 140). One exception is the response to PI3Kδ inhibitors in chronic lymphocytic leukaemia, where a combination of cell-intrinsic and -extrinsic activities drive efficacy. The p110δ-selective inhibitor GS-1101 (formerly known as CAL-101, and currently trade name as Zydelig approved on Jul. 23, 2014 by the U.S. Food and Drug Administration) produces dramatic responses in some B cell malignancies in combination with the anti-CD20 mAB rituximab (Drugs 2014, 74, 1701). This proves the principle that a potent and selective PI3K inhibitor can improve the survival of selected patient populations in cancer. However, GS-1101 has an unusual mechanism of action: the drug is not directly cytotoxic to malignant B lymphoma cells and its efficacy arises in part from modulating the immune environment of the tumour (Cancer Discov. 2011, 1, 562-572; Curr. Hematol. Malignancy Rep. 2013, 8, 22-27; Curr. Opin. Oncol. 2012, 24, 643-649). Recent preclinical studies further indicated that p100δ inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours (Nature 2014, 510, 407). Thus, there exists a need for novel selective inhibitors of class I PI3Ks. A novel PI3Kδ inhibitor could be used to understand the biology of the PI3K pathway in immune cells and in physiological models of tumour immunity (or immunology), and a novel PI3Kδ and/or a dual PI3Kδ/PI3Kγ inhibitor could have the potential therapeutic usefulness in immuno-oncology.
In addition, abundant evidence from genomic analysis has revealed that PI3K pathway is the most frequently mutated or altered pathway via PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) and PTEN (phosphatase and tensin homologin) in numerous forms of human cancers. Thus, a novel therapeutically effective inhibitor of PI3Ks is a promising therapeutic option, in association with known systemic cytotoxic and biological therapeutics, including immune checkpoint inhibitors, to overcome the often-rapid onset of resistance in responsive cancer patients based on emerging rational combination strategies, appropriate biomarkers and patient-specific mutation profiles (see: e.g., Nat. Rev. Drug Discov. 2014, 13, 140; Anticancer Research 2014, 34, 1493). Furthermore, a novel PI3K inhibitor, preferably with certain isoform selectivity patterns to minimize off-target effects, could be used to treat and prevent indications mediated by class I PI3Ks including inflammatory conditions, autoimmune conditions and angiogenesis. The present invention provides such compounds as further described below.